It has been recently recognized that chronic intermittent hypoxia (IH), as occurs in human obstructive sleep apnea (OSA), is associated with substantial cortico-hippocampal damage and leads to impairments in neurobehavioral functions. The objective of the current research application is to delineate the molecular mechanisms of reactive oxygen species (ROS) and antioxidant enzymes in the modulation and prevention of chronic IH-mediated neuronal cell vulnerability. The working hypothesis of the current application is that the cyclical oscillations of oxygen during IH mimics the ischemia (hypoxia)/re-oxygenation process and may increase cellular ROS production. The cumulative damage from oxidative propagation may result in neurological dysfunction. On the other hand, targeted increases in antioxidant enzymatic activity may reduce ROS-mediated propagation, decrease IH-mediated cortical neuronal cell death and prevent the neurobehavioral impairments. This proposal will therefore focus on the following specific aims: (1) To identify IH-mediated specific ROS production at specific cellular compartments of cortical neuronal cells and analyze the specific redox alterations in mitochondria, cytosol and membrane as they relate to neuronal cell vulnerability. (2) To analyze the molecular processes of ROS-mediated neuronal cell death induced by chronic IH, and delineate signal transduction pathways underlying neuronal cell death using cell culture and mouse models. (3) To define molecular relationships between chronic IH-mediated ROS production, protein aggregation, and neuronal cell vulnerability. Specifically, we will use primary cell culture and rodent models to elucidate the roles of protein oxidation and protein aggregation in the modulation of chronic IH-mediated neuronal cell death. (4). To study the protective roles of mitochondrial MnSOD and phospholipid glutathione peroxidase (GPX4) in primary neuronal cells in vitro and in vivo in response to chronic IH exposures. Specifically, we will use gene transfer, anti-sense, and transgenic mouse approaches to analyze the effects of increased/decreased mitochondrial anti-oxidant activity in preventing/facilitating chronic IH-mediated cortical neuronal cell death. We anticipate that increased understanding of the mechanisms underlying neuronal vulnerability to cyclical hypoxia will lead to delineation of effective interventional strategies aiming to reduce the substantial neurocognitive and behavioral morbidities associated with obstructive sleep apnea.